US6596706B1 - Piperazine-cyclodextrin complexes - Google Patents

Piperazine-cyclodextrin complexes Download PDF

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US6596706B1
US6596706B1 US09/530,592 US53059200A US6596706B1 US 6596706 B1 US6596706 B1 US 6596706B1 US 53059200 A US53059200 A US 53059200A US 6596706 B1 US6596706 B1 US 6596706B1
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Masahiko Kikuchi
Yukihiko Nagase
Kaneto Uekama
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Daiichi Pharmaceutical Co Ltd
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes

Definitions

  • the present invention relates to a piperazine-cyclodextrin complex which exhibits enhanced water solubility, excellent stability, and low topical stimulation and is useful as a therapeutic agent for circulatory diseases and diseases of the brain region.
  • Piperazine derivatives represented by the below-described formula (I) have been known to exhibit calmodulin-inhibition and to be useful as therapeutic agents for circulatory diseases and diseases of the brain region (Japanese Patent Application Laid-Open (kokai) No. 7-97364).
  • the piperazine derivatives (I) are difficult to be incorporated into an injection formulation. Even though an injection formulation is prepared from the piperazine derivatives (I), when the content of the derivatives increases, the formulation tends to provide topical stimulation due to hemolysis activity and vascular permeability attributed to the piperazine derivatives. Furthermore, there has also been a problem that the formulation has relatively low stability against light and its active component thereof is adsorbed on the container, depending on the material of the container, to thereby reduce the efficacy.
  • an object of the present invention is to provide a piperazine-cyclodextrin complex which exhibits enhanced water solubility, excellent stability, and low topical stimulation.
  • the present invention provides a piperazine-cyclodextrin complex formed of a piperazine derivative or a salt thereof and a water-soluble cyclodextrin derivative, wherein the piperazine derivative is represented by formula (I):
  • each of the aryl group, the heterocyclic group, and the aryl groups in the diarylmethyl group and the aralkyl group may have one or more substituents selected from among the following groups:
  • R represents a bicyclic nitrogen-containing heterocyclic group (i) or a phenyl group (ii), wherein the nitrogen-containing heterocyclic group has a condensed ring structure formed of a 5-membered ring and a 6-membered ring; one or two nitrogen atoms are contained in the 5-membered ring portion; the nitrogen-containing ring may be an aromatic or saturated ring; and the saturated ring may contain a ketone moiety; wherein the 5-membered ring portion of the bicyclic heterocyclic group (i) or the phenyl group (ii) is substituted with substituent G selected from the group consisting of the following groups:
  • a 5-membered aromatic heterocyclic group which may have a substituent and which contains as a heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding site for the nitrogen-containing heterocyclic group or for the phenyl group,
  • a 5-membered aromatic heterocyclic group which may have a substituent and which contains as a heteroatom one nitrogen atom and as a second heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the second heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding site for the nitrogen-containing heterocyclic group or for the phenyl group,
  • a 5-membered aromatic heterocyclic group which may have a substituent and which contains as heteroatoms two nitrogen atoms and as a third heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the third heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding site for the nitrogen-containing heterocyclic group or for the phenyl group,
  • heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which may have a substituent and contains as a heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group,
  • substituents are one or more members selected from the group consisting of the following substituents:
  • the 6-membered ring portion of the bicyclic heterocyclic group (i) or the phenyl group (ii) may have one or more groups selected from among a C1-C6 alkyl group, a C1-C6 alkoxyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a trifluoromethoxyl group, a 2,2,2-trifluoroethoxyl group, a C1-C6 alkylthio group, a C1-C6 alkylsulfinyl group, a C1-C6 alkylsulfonyl group, an alkanoyl group formed of a C1-C6 alkylene group and a carbonyl group, a C2-C7 alkanoyloxy group, a C2-C7 alkanoylamino group, an amino group, a monoalkylamino group having a C1-C6 alkyl groups, a dialkyla
  • the present invention also provides an injection formulation containing the piperazine-cyclodextrin complex.
  • the present invention also provides a therapeutic agent for circulatory diseases, a therapeutic agent for brain diseases, and a brain protecting agent containing the piperazine-cyclodextrin complex as an active component.
  • the present invention further provides use of the piperazine-cyclodextrin complex as a pharmaceutical.
  • the present invention still further provides a method for treatment of circulatory diseases and brain diseases, characterized by administration of the piperazine-cyclodextrin complex.
  • FIG. 1 is a graph showing the hemolysis activity data obtained in Example 2, in which ⁇ -cyclodextrin was added at a variety of concentrations.
  • FIG. 2 is a graph showing vascular permeability (expressed by dye-exuded area) in the case in which in Example 3 SEB7- ⁇ -CD was added at a variety of concentrations.
  • the piperazine derivative which is used in the present invention is represented by the above-described formula (I), and has a partial structure represented by Q connecting to one nitrogen atom of piperazine and a partial structure represented by R connecting to the other nitrogen atom via a linkage portion Z.
  • the partial structure Q represents a substituent selected from among (1) an aryl group, (2) a heterocyclic group, (3) a diarylmethyl group, (4) an aralkyl group formed of an aryl group and a C1-C6 alkylene group, (5) a C1-C8 alkyl group, or (6) a C3-C8 cycloalkyl group.
  • An aryl group is a substituent derived from an aromatic compound, and typical examples include a phenyl group and a naphthyl group. Although aromatic compounds also include heterocyclic compounds, the aryl group in the present invention refers particularly to a substituent derived from an aromatic hydrocarbon compound.
  • a heterocyclic group is a substituent derived from a heterocyclic compound.
  • nitrogen-containing heterocyclic compounds are preferred in the present invention.
  • nitrogen-containing heterocyclic compounds such as aromatic, partially saturated, and saturated species. Of these, aromatic heterocyclic compounds are preferred.
  • nitrogen-containing aromatic heterocyclic compounds examples include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, indole, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, naphthyridine, pyridopyridines, carbazole, carboline, phenanthridine, and acrydine.
  • the compounds of the present invention may have a substituent derived from these heterocyclic compounds. Among these substituents, a pyridyl group, a pyrimidyl group, and an isoquinolyl group are preferred.
  • heterocyclic groups containing an oxygen atom or a sulfur atom there may be used heterocyclic groups containing an oxygen atom or a sulfur atom.
  • the heterocyclic compounds may be aromatic, partially saturated, or saturated.
  • thienyl, benzothienyl, furyl, furanyl, benzofuranyl, or chromenyl may be used.
  • a group such as a benzofuranyl group or a dihydrobenzofuranyl group is preferred.
  • heterocyclic substituent containing a plurality of heteroatom species such as isothiazolyl, isoxazolyl, or oxazinyl.
  • the diarylmethyl group is a substituent in which two hydrogen atoms of the methyl group are substituted with two aryl groups.
  • the aryl groups may be those as described above.
  • the most typical diarylmethyl group is a diphenylmethyl group.
  • the aralkyl group formed of an aryl group and a C1-C6 alkylene group is a substituent in which one end of the alkylene group is bonded to the above-described aryl group.
  • Typical examples include a benzyl group and a phenethyl group.
  • the alkyl group may be a linear or branched C1-C8 alkyl group.
  • the cycloalkyl group may have 3-8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group.
  • Each of the above-described aryl groups, heterocyclic groups, diarylmethyl groups, C1-C8 alkyl groups, C3-C8 cycloalkyl groups, and aralkyl groups formed of an aryl group and a C1-C6 alkylene group may be substituted with a variety of substituents.
  • the aryl groups, the heterocyclic groups, and the aryl groups of the arylmethyl groups may have a substituent.
  • the substituents are selected from the following group consisting of substituents 1) through 29) below:
  • a C1-C6 alkyl group which may be liner or branched and may be a cycloalkyl group when it has three or more carbon atoms;
  • a C1-C6 alkoxyl group which may be formed of the above alkyl group and an oxygen atom, i.e., its alkyl moiety may be linear, branched or cyclic;
  • an alkylthio group which may be formed of the above C1-C6 alkyl group and a sulfur atom and has an “alkyl-S—” structure, wherein its alkyl moiety may be linear, branched or cyclic;
  • alkylsulfinyl group which is a substituent obtained through oxidation of the sulfur atom of the above alkylthio group by one oxygen atom and has an “alkyl-SO—” structure
  • alkylsulfonyl group which is a substituent obtained through oxidation of the sulfur atom of the above alkylthio group by two oxygen atoms and has an “alkyl-SO 2 —” structure;
  • alkanoyl group which is a substituent produced by removing a hydroxyl group from a carboxylic acid moiety of an aliphatic carboxylic acid and has an “alkyl-CO—” structure;
  • alkanoyloxy group which is a substituent having a structure of the above alkanoyl group to which an oxygen atom is added or a structure of a carboxylic acid moiety of an aliphatic carboxylic acid from which a hydrogen atom is removed, i.e., which alkanoyloxy group has an “alkyl-CO—O—” structure;
  • an alkanoylamino group which has a structure in which one of the two hydrogen atoms of its amino group is substituted with an alkanoyl group, i.e., an “alkyl-CO—NH—” structure;
  • a perfluoroalkyl group which has a structure in which all hydrogen atoms in its alkyl group are substituted, with a fluorine atom and has a linear, a branched, or a cyclic structure;
  • an alkoxycarbonyl group wherein its alkyl group and its carbonyl group are linked via an oxygen atom and its alkyl moiety may has a linear, a branched, or a cyclic structure, i.e., the alkoxycarbonyl group has an “alkyl-O—CO—” structure;
  • each of a methylenedioxy group, an ethylenedioxy group, and a propylenedioxy group has an —O—(CH 2 ) q —O—structure wherein q represents a number between 1 and 3 inclusive and two carbon atoms connecting with oxygen atoms are linked adjacently;
  • morpholinosulfonyl group which has a structure represented by “morpholino (i.e., 4-morphonyl group)-SO 2 —”;
  • a 4-alkylpiperazinosulfonyl group which has a structure represented by “(4-alkyl-1-piperazinyl)-SO 2 —” wherein the alkyl group connecting with the 4-position of the piperazinyl group is a C1-C6 alkyl group;
  • a 4-(dialkylamino)piperidino group which has a structure represented by “4-dialkylamino-1-piperidinyl” wherein the dialkylamino group connecting with the 4-position of the piperazinyl group has two C1-C6 alkyl groups which may be identical to or different from each other;
  • a 4-(monoalkylamino)piperidino group which has a structure represented by “4-monoalkylamino-1-piperidinyl” wherein the monoalkylamino group connecting with the 4-position of the piperazinyl group has a C1-C6 alkyl group;
  • One or more substituents may be selected from the group consisting of the above substituents. When two substituents are chosen, the substituents may be of a single species or a plurality of species.
  • the substituent selected from the group of the substituents may be bonded to the alkyl group or the cycloalkyl group of the substituents included in Q.
  • the moiety R of a bicyclic nitrogen-containing heterocyclic group (1) or a phenyl group (2) is bonded via a linkage moiety Z selected from among (1) a C1-C3 alkylene group, (2) a C2-C4 alkenylene group, (3) a C1-C3 alkylene group having one hydroxyl group, (4) a carbonyl moiety, (5) a C1-C2 alkylene group containing one carbonyl moiety at one end or an intermediate position of the carbon chain, or (6) an oxalyl group.
  • a linkage moiety Z selected from among (1) a C1-C3 alkylene group, (2) a C2-C4 alkenylene group, (3) a C1-C3 alkylene group having one hydroxyl group, (4) a carbonyl moiety, (5) a C1-C2 alkylene group containing one carbonyl moiety at one end or an intermediate position of the carbon chain, or (6) an oxalyl group.
  • alkylene group forming the moiety Z has the below-described formula:
  • the alkenylene group is a C2-C4 alkenylene group in which one carbon-carbon bond is a double bond which may exist at an end or an intermediate position.
  • the C1-C3 alkylene group having one hydroxyl group is a C1-C3 alkylene group in which one carbon atom has a hydroxyl group. No limitation is imposed on the position of the hydroxyl group, and it may exist at an end or an intermediate position.
  • the carbonyl moiety (or carbonyl group) has a structure represented by “—CO—.”
  • the C1-C2 alkylene group containing one carbonyl moiety at one end or an intermediate position of the carbon chain has one of the following structures:
  • the oxalyl group has a structure of “—CO—CO—.”
  • the partial structure represented by R comprises a bicyclic nitrogen-containing heterocyclic group (i) or a phenyl group (ii).
  • the bicyclic heterocyclic group has structural characteristics that (1) it has a condensed ring structure formed of a 5-membered ring and a 6-membered ring; (2) one or two nitrogen atoms are contained in the 5-membered ring portion; (3) the nitrogen-containing ring may be an aromatic or saturated ring; and (4) the saturated ring may contain a ketone moiety.
  • the heterocyclic group is a group derived from indole, isoindole, indazole, or benzo[d]imidazole.
  • groups derived from heterocyclic compounds containing an internuclear nitrogen atom such as indolidine, benzo[a]pyrazole, benzo[e]pyrazole, benzo[a]imidazole, or benzo[e]imidazole.
  • the hetrocyclic substituents are bonded to the above-mentioned linkage portion Z via a nitrogen atom or a carbon atom of the 5-membered ring.
  • heterocyclic substituents include indol-1-yl, indol-2-yl, indol-3-yl, 2,3-dihydroindol-1-yl, 2,3-dihydroindol-2-yl, 2,3-dihydroindol-3-yl, 3H-indol-2-yl, 3H-indol-3-yl, 2-oxoindol-1-yl, 2-oxoindol-3-yl, indazol-1-yl, indazol-3-yl, 2,3-dihydroindazol-1-yl, 2,3-dihydroindazol-2-yl, 2,3-dihydroindazol-3-yl, 3H-indazol-3-yl, 2,3-dihydro-3-oxoindazol-1-yl, 2,3-dihydro-3-oxoindazol-2-yl, 2,3
  • substituent G selected from the group consisting of the following groups.
  • R is a phenyl group
  • a particularly preferable substitution site is a carbon atom adjacent to the carbon atom connecting with the moiety Z, i.e. an ortho position.
  • the portion R is a heterocyclic substituent
  • a preferable substitution site is in the nitrogen-containing 5-membered ring portion. In this case, the site may be a nitrogen atom or a carbon atom.
  • (aa) a C1-C6 alkyl group, which may be cyclic, linear, or branched;
  • a 5-membered aromatic heterocyclic group which may have a substituent and which contains as a heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding site for the nitrogen-containing heterocyclic group or for the phenyl group, examples of the 5-membered aromatic heterocyclic group including a pyrrolyl group, a furyl group, and a thienyl group.
  • This substituent may be bonded to the bicyclic nitrogen-containing heterocyclic group or phenyl group at any of possible sites thereof;
  • a 5-membered aromatic heterocyclic group which may have a substituent and which contains as a heteroatom one nitrogen atom and as a second heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the second heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding site for the nitrogen-containing heterocyclic group or for the phenyl group, examples of the 5-membered aromatic heterocyclic group including a pyrazolyl group, a imidazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, and an isoxazolyl group.
  • This substituent may be bonded to the bicyclic nitrogen-containing heterocyclic group or phenyl group at any of possible sites thereof;
  • a 5-membered aromatic heterocyclic group which may have a substituent and which contains as heteroatoms two nitrogen atoms and as a third heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the third heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding site for the nitrogen-containing bicyclic heterocyclic group or for the phenyl group, examples of the 5-membered aromatic heterocyclic group including a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a 1,2,3-thiadiazyl group, a 1,2,4-thiadiazyl group, a 1,2,5-thiadiazyl group, a 1,3,4-thiadiazyl group, a 1,2,3-oxadiazyl group, a 1,2,4-oxadiazyl group, a 1,2,5-oxadiazyl group, a
  • a 6-membered aromatic heterocyclic group which may have a substituent and which contains one or two nitrogen atoms, examples of the 6-membered aromatic heterocyclic group including a pyridyl group, a pyridazinyl group, a pyrimidyl group, and a piradinyl group.
  • This substituent may be bonded to the bicyclic nitrogen-containing heterocyclic group or phenyl group at any of possible sites thereof;
  • heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which 5-membered aromatic heterocyclic group may have a substituent and contains as a heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, examples of the heterocyclic group-substituted alkyl group including a pyrrolyl-methyl-ethyl or propyl group, a thienyl-methyl-ethyl or propyl group, and a furyl-methyl, ethyl or propyl group, wherein the alkylene group may be bonded to any possible bonding site of the heterocyclic moiety;
  • heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which 5-membered aromatic heterocyclic group may have a substituent and contains as heteroatoms two nitrogen atoms and as a third heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the third heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding site for the alkylene group, examples of the heterocyclic group-substituted alkyl group including a 1,2,3-triazolyl-methyl, ethyl, or propyl group, a 1,2,4-triazolyl-methyl, ethyl, or propyl group, a 1,2,3-thiadiazyl-methyl, ethyl, or propyl group, a 1,2,4-
  • examples of the 6-membered aromatic heterocyclic group including a pyridyl-methyl, ethyl, or propyl group, a pyridazinyl-methyl, ethyl, or propyl group, a pyrimidyl-methyl, ethyl, or propyl group, and a piradinyl-methyl, ethyl, or propyl group wherein the alkylene group may be bonded to any possible bonding site of the heterocyclic moiety;
  • a phenylhydroxyalkyl group formed of a C2-C3 alkylene group having one hydroxyl group and a phenyl group which may have a substituent, examples thereof including a 1-hydroxy-2-phenylethyl group, a 2-hydroxy-2-phenylethyl, 1-hydroxy-3-phenylpropyl group, a 2-hydroxy-3-phenylpropyl group, and a 3-hydroxy-3-phenylpropyl group;
  • a tetrazolylalkyl group formed of a tetrazolyl group and a C1-C3 alkylene group wherein the alkylene group is bonded to the carbon atom or a nitrogen atom of the tetrazolyl group, examples thereof including a tetrazolyl-methy, ethyl, or propyl group;
  • a morpholinoalkyl group formed of a morpholino group and a C1-C3 alkylene group, examples thereof including a morpholino-methy, ethyl, or propyl group;
  • alkoxycarbonylalkyl group formed of a C1-C3 alkylene group and an alkoxycarbonyl group wherein its alkoxyl group has one to six carbon atoms, examples thereof including an alkoxycarbonyl-methy, ethyl, or propyl group;
  • a 1,4-dihydropyridyl group which may have a substituent such as alkyl groups and carboxyl groups, examples thereof including a 2,6-bis(methoxycarbonyl)-3,5-dimethyl-1,4-dihydropyridyl group;
  • substituents listed in the above substituent group refers to that the substituent may have a substituent selected from among the below-described substituent group.
  • substituents may be selected from the group consisting of the below-described substituents:
  • the 6-membered ring portion of the bicyclic heterocyclic group (i) or the phenyl group (ii) may have one or more groups selected from among a C1-C6 alkyl group, a C1-C6 alkoxyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a trifluoromethoxyl group, a 2,2,2-trifluoroethoxyl group, a C1-C6 alkylthio group, a C1-C6 alkylsulfinyl group, a C1-C6 alkylsulfonyl group, an alkanoyl group formed of a C1-C6 alkylene group and a carbonyl group, a C2-C7 alkanoyloxy group, a C2-C7 alkanoylamino group, an amino group, a monoalkylamino group having a C1-C6 alkyl group, a dialkylamin
  • nitrogen-containing bicyclic heterocyclic groups serving as substituents R include groups having a structure represented by the following formula:
  • each of R 1 and R 2 which may be identical to or different from each other, represents a group selected from among a C1-C6 alkyl group, a C1-C6 alkoxyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a trifluoromethoxyl group, a 2,2,2-trifluoroethoxyl group, a C1-C6 alkylthio group, a C1-C6 alkylsulfinyl group, a C1-C6 alkylsulfonyl group, an alkanoyl group formed of a C1-C6 alkylene group and a carbonyl group, a C2-C7 alkanoyloxy group, a C2-C7 alkanoylamino group, an amino group, a monoalkylamino group having a C1-C6 alkyl group, a dialkylamin
  • R 1 , R 2 , and G have the same meanings as described above.
  • nitrogen-containing bicyclic heterocyclic groups having a preferable structure examples include groups represented by the following formula:
  • substituent G may be bonded to the 2- position of indazole.
  • An indazole structure or a phenyl group structure is preferred as the substutuent R. Of these an indazole structure is more preferred.
  • substituent R is an indazole
  • substituent G connecting with the substituent R include groups which are already defined above as G and are selected from among the following:
  • heterocyclic group-substituted alkylene group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which 5-membered aromatic heterocyclic group may have a substituent and contains as a heteroatom a nitrogen atom, a sulfur atom, or an oxygen atom,
  • heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which 5-membered aromatic heterocyclic group may have a substituent and contains one nitrogen atom and as a second heteroatom a nitrogen atom, a sulfur atom, or an oxygen atom,
  • heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which 5-membered aromatic heterocyclic group may have a substituent and contains two nitrogen atoms and as a second heteroatom a nitrogen atom, a sulfur atom, or an oxygen atom,
  • heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 6-membered aromatic heterocyclic group, which 6-membered aromatic heterocyclic group may have a substituent and contains one or two nitrogen atoms,
  • a phenylhydroxyalkyl group formed of a C1-C3 alkylene group having one hydroxyl group and a phenyl group which may have a substituent
  • a tetrazolylalkyl group formed of a C1-C3 alkylene group
  • a morpholinoalkyl group formed of a morpholino group and a C1-C3 alkylene group
  • alkoxycarbonylalkyl group formed of a C1-C6 alkoxyl group, a carbonyl group, and a C1-C3 alkylene group
  • a pyrrolidon-2-yl group which may have a substituent, a (2-guanidinothiazolyl)alkyl group formed of a 2-guanidinothiazolyl group and a C1-C3 alkylene group,
  • alkoxycarbonylalkyl group formed of a C1-C6 alkoxyl group, a carbonyl group, and a C1-C6 alkylene group
  • a [4-(4-aminopiperidino)phenyl]alkyl group formed of a C1-C6 alkylene group and a 4-(aminopiperidino)phenyl group wherein a 4-aminopiperidino group having, at the 4-position of piperidine, an amino group is bonded to the 4-position of the phenyl group,
  • a (4-dialkylaminopiperidino)alkyl group formed of a C1-C6 alkylene group and a 4-dialkylaminopiperidino group wherein a dialkylamino group having two C1-C6 alkyl groups which may be identical to or different from each other is bonded to the 4-position of piperidine,
  • a (4-monoalkylaminopiperidino)alkyl group formed of a C1-C6 alkylene group and a 4-monoalkylaminopiperidino group wherein a monoalkylamino group having a C1-C6 alkyl group is bonded to the 4-position of piperidine,
  • a (4-aminopiperidino)alkyl group formed of a C1-C6 alkylene group and a 4-aminopiperidino group having an amino group at the 4-position of piperidine,
  • a phenylalkyl group formed of a C1-C6 alkylene group and a phenyl group which may have a substituent
  • heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which 5-membered aromatic heterocyclic group may have a substituent and contains as a heteroatom a nitrogen atom, a sulfur atom, or an oxygen atom,
  • heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group which 5-membered aromatic heterocyclic group may have a substituent and contains one nitrogen atom and as a second heteroatom a nitrogen atom, a sulfur atom, or an oxygen atom
  • a heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group which 5-membered aromatic heterocyclic group may have a substituent and contains two nitrogen atoms and as a second heteroatom a nitrogen atom, a sulfur atom, or an oxygen atom
  • heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 6-membered aromatic heterocyclic group, which 6-membered aromatic heterocyclic group may have a substituent and contains one or two nitrogen atoms,
  • substituent R contains an indazole group
  • substituent G connecting with the substituent R is a heterocyclic group-substituted alkyl group or a phenylalkyl group.
  • a compound having a hydrogen atom serving as the substituent G is one of the preferable compounds in that it exhibits strong calmodulin-inhibition.
  • the substituent G When the substituent R contains an indazole, preferable examples of the substituent G include an aralkyl group formed of an aryl group and a C1-C6 alkylene group.
  • the aryl group contained in the aralkyl group includes a heterocyclic group derived from an aromatic heterocyclic compound as well as a substituent derived from an aromatic hydrocarbon compound. Examples of the aralkyl group include the following:
  • heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which 5-membered aromatic heterocyclic group may have a substituent and contains as a heteroatom a nitrogen atom, a sulfur atom, or an oxygen atom,
  • heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which 5-membered aromatic heterocyclic group may have a substituent and contains one nitrogen atom and as a second heteroatom a nitrogen atom, a sulfur atom, or an oxygen atom,
  • heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which 5-membered aromatic heterocyclic group may have a substituent and contains two nitrogen atoms and as a second heteroatom a nitrogen atom, a sulfur atom, or an oxygen atom,
  • heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 6-membered aromatic heterocyclic group, which 6-membered aromatic heterocyclic group may have a substituent and contains one or two nitrogen atoms,
  • a phenylhydroxyalkyl group formed of a C2-C3 alkylene group having one hydroxyl group and a phenyl group which may have a substituent
  • a tetrazolylalkyl group formed of a C1-C3 alkylene group and a tetrazolyl group wherein the alkylene group is bonded to a carbon atom or a nitrogen atom of the tetrazolyl group,
  • a morpholinoalkyl group formed of a morpholino group and a C1-C3 alkylene group
  • a phenylalkyl group formed of a C1-C6 alkylene group and a phenyl group which may have a substituent.
  • an aralkyl group having a C1 or C2 alkylene group is preferred, and that having a C1 alkylene group, i.e., an arylmethyl group, is more preferred.
  • the aryl group also includes a heterocyclic aryl group in addition to a hydrocarbonic aryl group.
  • the substituent R contains an indazole
  • the indazole may have a substituent.
  • examples of the preferable substituent include groups selected from among the following groups:
  • alkanoyl group formed of a C1-C6 alkyl group and a carbonyl group
  • each of the alkyl groups is a C1-C6 alkyl group
  • substituent R contains an indazole
  • substituent R contains an indazole
  • substituent R contains an indazole
  • substituent R contains an indazole
  • halogen atom preferably a fluorine atom
  • each alkyl group is independently a C1-C6 alkyl group
  • substituent R is a phenyl group
  • substituent G connecting with the phenyl group include groups selected from among the following:
  • a phenyl group which may have a substituent, a 5-membered aromatic heterocyclic group which may have a substituent and which contains as a heteroatom a nitrogen atom, a sulfur atom, or an oxygen atom,
  • a 5-membered aromatic heterocyclic group which may have a substituent and which contains one nitrogen atom and as a second heteroatom a nitrogen atom, a sulfur atom, or an oxygen atom,
  • a 5-membered aromatic heterocyclic group which may have a substituent and which contains two nitrogen atoms and as a second heteroatom a nitrogen atom, a sulfur atom, or an oxygen atom,
  • a morpholinoalkyl group consisting of a morpholino group and a C1-C3 alkylene group
  • the substituent R is a phenyl group
  • an aryl group is preferred with regard to the substituent G connecting with the substituent R.
  • the aryl group also includes a heterocyclic aryl group in addition to a hydrocarbonic aryl group.
  • the substituent R is a phenyl group
  • the phenyl group may have one or more substituents.
  • the preferable substituents include the same groups as described in the case in which the substituent R contains an indazole.
  • Examples of the preferable structures as the substituent R include an indazole structure having two methoxyl groups or a methylenedioxy group or a phenyl group structure having two methoxyl groups or a methylenedioxy group.
  • an aryl group is preferred.
  • a phenyl group is preferred as the aryl group.
  • the phenyl group may have one or more substituents.
  • the phenyl group is preferably substituted at a m-position, which is defined to the bonding site of the phenyl group with piperazine.
  • a halogen atom is preferable for the meta substituent, with a chlorine atom and a trifluoromethyl group being more preferable.
  • the phenyl group When the meta substituent is a halogen atom, the phenyl group may have an alkyl group as a second substituent, whereas when it is a trifluoromethyl group, the phenyl group may have an alkoxyl group as a second substituent.
  • an electron-withdrawing substituent is suitable for the meta substituent
  • an electron-donating group is suitable for the second substituent
  • an alkylene group is preferred among the above-described groups.
  • a C2 or C3 alkylene group is preferred, with the C2 alkylene group being more preferred.
  • a typical example of a salt of the piperazine derivative (I) is an acid-adduct-type salt.
  • the acid which is added in order to produce the salt may both be an inorganic acid and an organic acid.
  • the inorganic acid include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.
  • Carboxylic acids and sulfonic acids may be used as the organic acid, and examples thereof include acetic acid, propionic acid, lactic acid, maleic acid, fumaric acid, and methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid, respectively. It is apparent that a compound of the piperazine derivative (I) can be used in the human body so long as the acid which forms the acid-adduct-type salt is harmless to the human body.
  • the piperazine derivative (I) contains an acidic moiety such as a carboxylic group or a sulfonyl group, the derivative can form a salt with a base via the acidic moiety.
  • the piperazine derivative (I) may take a hydrate form or a solvated form.
  • the hydrate and the solvate include both that of the free compound of the formula (I) and a salt of the compound of the formula (I). They also include a tautomer of the compound of the formula (I).
  • piperazine derivative (I) include the following compounds:
  • more preferable example includes the folowing compounds:
  • the piperazine derivative (I) may be produced through a method described in, for example, Japanese Patent Application Laid-Open (kokai) No. 7-97364.
  • the water-soluble cyclodextrin derivative which is used in the present invention refers to a derivative having water solubility greater than that of ⁇ -cyclodextrin.
  • Examples of the derivative include compounds represented by formula (II):
  • m represents an integer between 6 and 12 inclusive and each of R 3 , R 4 , and R 5 , which may be identical to or different from one another in each of the recurring units, represents a hydrogen atom, a sulfoalkyl group, a hydroxyalkyl group, or a sugar residue.
  • variable m represents an integer between 6 and 12 inclusive, preferably between 6 and 9 inclusive, particularly 7, i.e., a ⁇ -cyclodextrin derivative.
  • sulfoalkyl group examples include sulfoalkyl groups having a C1-C6 alkyl group such as a sulfomethyl group, a sulfoethyl group, a sulfopropyl group, or a sulfobutyl group, with a sulfobutyl group being particularly preferable.
  • hydroxyalkyl group examples include hydroxyalkyl groups having a C1-C6 alkyl group such as a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, or a hydroxybutyl group, with a hydroxypropyl group being particularly preferable.
  • sugar residues having 3-24 carbon atoms are preferred, and those having 6-12 carbon atoms are particularly preferred.
  • the residue include a glucosyl group, a galactosyl group, a glycero-gluco-heptosyl group, a maltosyl group, and a lactosyl group, with a maltosyl group being more preferred.
  • the water-soluble cyclodextrin derivative represented by formula (II) has a substitution ratio, i.e., a ratio of a substituent other than a hydrogen atom to the sum of R 3 , R 4 , and R 5 in the water-soluble cyclodextrin derivative represented by formula (II), of preferably 70% or less, particularly preferably 20-50%.
  • water-soluble cyclodextrin derivative there may also be used suitable cyclodextrins described in, for example, Japanese Kohyo Patent Publication Nos. 5-504783 (WO91/11172) and 6-511513 (W094/02518).
  • water-soluble cyclodextrin derivative examples include sulfobutylcyclodextrin, hydroxypropylcyclodextrin, maltosylcyclodextrin, and salts thereof.
  • sulfobutyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, maltosyl- ⁇ -cyclodextrin, and salts thereof are preferred.
  • sulfobutyl- ⁇ -cyclodextrin or hydroxypropyl- ⁇ -cyclodextrin and salts thereof having a substitution ratio of 70% or less, particularly 20-50% are preferred, and a ⁇ -cyclodextrin sulfobutylether sodium salt having a substitution ratio of approximately 33% and hydroxypropyl- ⁇ -cyclodextrin having a substitution ratio of approximately 23% are more preferred.
  • the piperazine-cyclodextrin complex of the present invention may be obtained by producing an aqueous solution containing the piperazine derivative (I) or a salt thereof and a water-soluble cyclodextrin derivative.
  • the freely water-soluble cyclodextrin derivative is used in an amount of preferably one mol or more based on one mol of the piperazine derivative (I) or a salt thereof, particularly preferably 1-10 mol.
  • the higher the concentration of the water-soluble cyclodextrin derivative the more the solubility of the piperazine derivative (I) increases.
  • No particular limitation is imposed on the method for producing the aqueous solution, and for example it is produced by use of water or a buffer in a temperature range approximately from ⁇ 5 to 35° C.
  • the thus-obtained piperazine-cyclodextrin complex of the present invention may be used as such or in a powder form which is obtained by removing co-existing water.
  • Examples of the method for removing water include lyophilization and drying under reduced pressure.
  • a powder product obtained from lyophilization is particularly preferred.
  • the piperazine-cyclodextrin complex of the present invention exhibits its effects through either oral administration or parenteral administration, and it is preferably formed into a formulation for parenteral administration, particularly an injection formulation.
  • the dose of the complex of the present invention may be modified appropriately in accordance with the age, body weight, and severity of the patient's symptom.
  • the daily dose for an adult, reduced as the piperazine derivative (I) is 1 mg to 1000 mg, preferably 10 mg to 500 mg, and the complex may be administered at a single time or in a divided manner.
  • the form of formulation include tablets, capsules, powders, and granules. These may be produced through a known technique by use of typical additives such as excipients, lubricants, and binders.
  • the daily dose for an adult, reduced as the piperazine derivative (I), is 1 mg to 500 mg, preferably 10 mg to 200 mg, and preferably, the complex is administered at the dose through hypodermic injection, intravenous injection or intravenous drip.
  • the piperazine-cyclodextrin complex of the present invention exhibits excellent calmodulin-inhibition and has excellent antihypoxia action. Moreover, it exhibits excellent efficacy against a variety of pathologic models (such as inhibition to late neurocyte death or antiedemic action of jirds) through peroral and parenteral administration at a dose which causes no central inhibition.
  • pathologic models such as inhibition to late neurocyte death or antiedemic action of jirds
  • the piperazine-cyclodextrin complex of the present invention serves as an inhibitor for calmodulin-induced physiological action caused by intracellar calcium, and is useful as a therapeutic agent, particularly as a therapeutic agent and a preventive agent for a variety of diseases induced by excessive activation of calmodulin such as hypertension and ischemic diseases of the brain, heart, and kidney such as cerebral infarction, cerebral embolism, transient ischemic attack, cerebral thrombosis, cardiac infarction, angina pectoris, cardiac failure, acute renal failure, or nephritis; diseases of the brain region such as Alzheimer's disease, Parkinson disease, or Binswanger's disease; drug intoxication; gassing; traumatic brain diseases and diseases caused thereby such as aspontaneity, depression, or memory disorder.
  • the complex is particularly useful as a therapeutic agent for circulatory diseases and brain diseases or as a brain-protective agent.
  • the mixture was allowed to stand for 7 days in a 25° C. water bath. During the standing period, the mixture was sonicated once a day for 15 minutes, followed by stirring for 2 minutes. On the first, fifth, and seventh days, pH of the mixture was adjusted to 4.0 by addition of adequate amount of HCl. After pH was adjusted on the seventh day, the amount of the entirety of the mixture was adjusted to 5 ml (to thereby achieve a SBE7- ⁇ -CD concentration of 15, 20, or 30 mM). Six days later, the mixture was subjected to centrifugal separation, to thereby collect a supernatant.
  • aqueous solution having a composition shown in Table 2 was prepared.
  • the solution was subcutaneously injected to the back of a rat. Thirty minutes after injection, a 0.5% Evans blue solution was intravenously injected, and 30 minutes thereafter, the area of the skin in which the dye exuded was measured to check vascular permeability.
  • FIG. 2 shows that the vascular permeability caused by complex compound (1) and SBE7- ⁇ -CD was lower than that of compound (1).
  • aqueous solution having a composition shown in Table 3 was prepared, and 10 ml-aliquots were individually put into ampules.
  • the solution was prepared as follows.
  • the compound (1) (2.55 g) was dissolved in water for injection (700 ml).
  • SBE7- ⁇ -CD (18.04 g) was dissolved in water for injection (200 ml), and the solutions were mixed.
  • the pH was adjusted, and then water for injection was added so as to make the volume of the entirety equal to 1 liter.
  • the complex of the present invention is excellent in terms of stability against photolytic stress.
  • Solutions A and B prepared in Example 4 were respectively diluted with a transfusion EL-1 (product of Morishita-Roussel) so that the concentration of compound (1) became 20 ⁇ g/ml.
  • the solution was placed in a dripping tube (made of polyvinyl chloride) of a transfusion set, and stored for 2 hours under light-shielded conditions at 25° C.
  • the compound (1) content of the diluted solution after storage was quantitatively determined by high performance liquid chromatography (HPLC) under the same conditions as described in Example 1.
  • the recovery rate of compound (1) was 102% for the case of solution A and 87% for the case of solution B.
  • the complex of the present invention was proven to exhibit improved adsorption onto the transfusion set.
  • the piperazine-cyclodextrin complexes of the present invention exhibit remarkably improved solubility as compared with the case of a sole use of piperazine derivative (I). Also, they suppress hemolysis activity and vascular permeability, and exhibit reduced local stimulation. Moreover, they exhibit excellent stability against photolytic stress and reduced adsorption onto the container therefor.

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US20070066821A1 (en) * 2005-09-16 2007-03-22 Allison Brett D Cyclopropyl amines as modulators of the histamine h3 receptor
US20100113472A1 (en) * 2008-11-03 2010-05-06 Chemocentryx, Inc. Compounds for the treatment of osteoporosis and cancers
US20110013686A1 (en) * 2003-02-18 2011-01-20 Qualcomm Incorporated Systems and methods for improving channel estimation
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BR0116658A (pt) * 2001-01-04 2003-12-30 Daiichi Seiyaku Co Preparação farmacêutica contendo ciclodextrina
US6982256B2 (en) 2001-09-07 2006-01-03 Boehringer Ingelheim Pharma Kg Tolerance of 4-(4-(2-pyrrolylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine in intravenous administration
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US20040110746A1 (en) * 2002-10-23 2004-06-10 Apodaca Richard L. Piperazinyl and diazapanyl benzamides and benzthioamides
US20080056991A1 (en) * 2002-10-23 2008-03-06 Apodaca Richard L Piperazinyl and diazapanyl benzamides and benzthioamides
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US20110013686A1 (en) * 2003-02-18 2011-01-20 Qualcomm Incorporated Systems and methods for improving channel estimation
US20070066821A1 (en) * 2005-09-16 2007-03-22 Allison Brett D Cyclopropyl amines as modulators of the histamine h3 receptor
US7687499B2 (en) 2005-09-16 2010-03-30 Janssen Pharmaceutica Nv Cyclopropyl amines as modulators of the histamine H3 receptor
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US20100113472A1 (en) * 2008-11-03 2010-05-06 Chemocentryx, Inc. Compounds for the treatment of osteoporosis and cancers
EP3903822A4 (en) * 2018-12-27 2022-08-31 National University Corporation Kumamoto University BRAIN PENETRATING LIGAND AND DRUG CARRIER

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